Hereditary non-polyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes. Tumors that develop in a person with HNPCC have a very large number of microsatellite instability (MSI). Approximately 15% of all colorectal cancers have MSI and in most instances this is due to acquired genetic defects in the DNA MMR system, rather than a germline mutation. Therefore, in addition to being perhaps the most common form of an inherited predisposition to cancer, HNPCC has been a model for the understanding of genomic instability in sporadic tumors. We are interested in HNPCC for two reasons. First, our laboratory has established in vitro models in which to study the biology of normal DNA MMR activity and how mutations in the MMR genes affect the cell cycle. Secondly, as a laboratory dedicated to transnational investigation, we are interested in the clinical side of HNPCC. A central theme of this application is that we can find the germline basis of HNPCC in only about half of such families. We have hypothesized that there are additional genes participating in the DNA MMR system that may be responsible for HNPCC. We have data suggesting that there is another DNA MMR gene on chromosome 3. We have hypothesized that different types of mutations in the known HNPCC genes alter the DNA MMR system in different ways which may be responsible for the various phenotypes seen in this disease. We are part of the UC Irvine-UC San Diego collaborative Cancer Genetics Network, which will provide us with a large data base of familial colorectal tumors. We will use this data base to obtain tumor tissue and blood from patients with familial forms of colorectal cancer. We will first determine whether all colorectal cancers can be divided into one of the two known mechanisms of genomic instability. We will look for new germline mutations that might be responsible for HNPCC. Finally, we will microdissect tumors with MSI and determine which genes are mutated in the tumor progression sequence. We have hypothesized that the traditional "gatekeepers" for adenoma formation and conversion to carcinoma may not be the same as those that occur in tumors without MSI. In summary, we propose to study the basic biology of the DNA MMR system in vitro, and use this information to develop insight into the clinical behavior and the diagnostic strategies for HNPCC, predisposition to cancer, HNPCC, has been a model for understanding genomic instability in sporadic tumors.